Article

Circulating Myeloid-Derived Suppressor Cells Are Increased and Activated in Pulmonary Hypertension

Department of Pediatrics, Division of Pulmonary and Critical Care Medicine, University of Colorado, Denver, Aurora, CO 80045, USA.
Chest (Impact Factor: 7.13). 09/2011; 141(4):944-52. DOI: 10.1378/chest.11-0205
Source: PubMed

ABSTRACT Myeloid-derived suppressor cells (MDSCs) are increased in inflammatory and autoimmune disorders and orchestrate immune cell responses therein. Pulmonary hypertension (PH) is associated with inflammation, autoimmunity, and lung vascular remodeling. Immature myeloid cells are found in the lungs of humans and animals with PH, and we hypothesized that they would be increased in the blood of patients with PH compared with control subjects.
Twenty-six children with PH and 10 undergoing cardiac catheterization for arrhythmia ablation were studied. Five milliliters of fresh blood were analyzed using flow cytometry. Results were confirmed using magnetic bead sorting and immunofluorescence, while quantitative polymerase chain reaction and intracellular urea concentration assays were used as measures of MDSC arginase-1 activation.
Flow cytometry demonstrated enrichment of circulating MDSCs among patients with PH (n = 26; mean, 0.271 × 10(6) cells/mL ± 0.17; 1.86% of CD45(+) population ± 1.51) compared with control subjects (n = 10; mean, 0.176 × 10(6) cells/mL ± 0.05; 0.57% of CD45(+) population ± 0.29; P < .05). Higher numbers of circulating MDSCs correlated to increasing mean pulmonary artery pressure (r = 0.510, P < .05). Among patients with PH, female patients had a twofold increase in MDSCs compared with male patients. Immunofluorescence analysis confirmed the results of flow cytometry. Quantitative reverse transcription polymerase chain reaction assay results for arginase-1 and measurement of intracellular urea concentration revealed increased activity of MDSCs from patients with PH compared with control subjects.
Circulating activated MDSCs are significantly increased in children with PH compared with control subjects. Further investigation of these cells is warranted, and we speculate that they might play significant immunomodulatory roles in the disease pathogenesis of PH.

0 Followers
 · 
141 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Analysis of the human proteome has become increasingly sophisticated, and offers invaluable potential insight into the pathophysiology of human disease. The increasing standardization of methods, speed and sophistication of mass spectrometric analysis, availability of reliable antibodies and dissemination of information among the scientific community has allowed for exponential growth of our knowledge base. The continued effort to provide a molecular explanation for future medical applications based on biomarker discovery is epitomized by the outstanding efforts of the human proteome project, whose goal is to generate a map of the human proteome. However, proteomic analysis is underrepresented in pediatric illness; given the unique challenges of research in the pediatric population, proteomic analysis represents enormous untapped potential, especially in the further elucidation of the pathophysiology of rare diseases such as pulmonary hypertension (PH). In this article we will describe the unique challenge of pediatric research, the importance of alternative avenues such as proteomics for in depth analysis of pediatric pathobiology at the cellular level, the specific need for proteomic investigation of pediatric PH, the current status of PH proteomics and future directions.This article is protected by copyright. All rights reserved
    PROTEOMICS - CLINICAL APPLICATIONS 12/2014; 8(11-12). DOI:10.1002/prca.201400067 · 2.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary hypertension (PH) is characterized by increased proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs). Forkhead box O (FoxO) transcription factors are key regulators of cellular proliferation. Here we show that in pulmonary vessels and PASMCs of human and experimental PH lungs, FoxO1 expression is downregulated and FoxO1 is inactivated via phosphorylation and nuclear exclusion. These findings could be reproduced using ex vivo exposure of PASMCs to growth factors and inflammatory cytokines. Pharmacological inhibition and genetic ablation of FoxO1 in smooth muscle cells reproduced PH features in vitro and in vivo. Either pharmacological reconstitution of FoxO1 activity using intravenous or inhaled paclitaxel, or reconstitution of the transcriptional activity of FoxO1 by gene therapy, restored the physiologically quiescent PASMC phenotype in vitro, linked to changes in cell cycle control and bone morphogenic protein receptor type 2 (BMPR2) signaling, and reversed vascular remodeling and right-heart hypertrophy in vivo. Thus, PASMC FoxO1 is a critical integrator of multiple signaling pathways driving PH, and reconstitution of FoxO1 activity offers a potential therapeutic option for PH.
    Nature Medicine 10/2014; 20(11). DOI:10.1038/nm.3695 · 28.05 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: Partial bladder outlet obstruction causes a significant increase in tissue and systemic oxidative stress markers and tissue inflammatory cytokine levels. Myeloid-derived suppressor cells, IFN-gamma, IL-10 and aldosterone are believed to be associated with oxidative stress and inflammation. We investigated alterations in plasma myeloid-derived suppressor cells, IFN-gamma, IL-10 and aldosterone levels in partial bladder outlet obstruction and after its reversal. Materials and Methods: Rats with surgically induced partial bladder outlet obstruction were divided into 4 groups of 3 each, including sham treated, 4-week obstruction, and 4 and 8-week obstruction with relief. Plasma levels of circulating myeloid-derived suppressor cells, IFN-gamma, IL-10 and aldosterone were assessed by flow cytometry or enzyme-linked immunosorbent assay. Results: The circulating myeloid-derived suppressor cell level was markedly increased in the obstruction group compared to the sham treated group and it returned to normal in the 4 and 8-week obstruction with relief groups. Plasma IFN-gamma, IL-10 and aldosterone were similarly increased in the obstruction group and returned to normal in the 4 and 8-week obstruction with relief groups. Conclusions: Levels of circulating myeloid-derived suppressor cells, IFN-gamma, IL-10 and aldosterone were increased in rats with partial bladder outlet obstruction but returned to normal after reversal. This suggests that an increase in these parameters may be a good predictive indicator of patients at increased risk for urinary symptoms.
    The Journal of Urology 05/2014; 192(5). DOI:10.1016/j.juro.2014.05.045 · 3.75 Impact Factor

Full-text

Download
75 Downloads
Available from
Jun 1, 2014